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METTL3 regula la heterocromatina en las células madre embrionarias de ratón

Wenqi Xu^1,2,3, Jiahui Li^1,2, Chenxi He^1,2

¹Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.

|January 28, 2021

Resumen

La metiltransferasa tipo 3 (METTL3) regula la integridad de la heterocromatina de las células madre embrionarias de ratón. La metilación del ARN mediada por METTL3 es crucial para silenciar los retrovirus endógenos y el desarrollo de los mamíferos.

Área de la Ciencia:

Epigenética y regulación genética
Biología del ARN
Desarrollo de los mamíferos

Sus antecedentes:

Se sabe que la metiltransferasa 3 (METTL3) metila el ARNm en el sitio de la N6-metiladenosina (m6A), influyendo en la estabilidad y la traducción del ARNm.
El papel de METTL3 en la unión de la cromatina y su impacto en la heterocromatina, en particular con respecto a los retrovirus endógenos, sigue siendo incompleto.

Objetivo del estudio:

Investigar la función de la metilación de METTL3 y m6A en la regulación de la integridad de la heterocromatina en las células madre embrionarias de ratón.
Aclarar el mecanismo por el cual METTL3 controla los elementos retrovirales endógenos dentro del genoma.

Principales métodos:

Análisis de la localización y función de METTL3 en células madre embrionarias de ratón, centrándose en los retrovirus de partículas A intracisternas (IAP).
Investigación de la deposición de la marca de la heterocromatina, la transcripción retroviral y la interacción de METTL3 con las transcripciones de ARN y las proteínas modificadoras de la cromatina (SETDB1, TRIM28).
Se utilizó el lector de m6A YTHDC1 para estudiar su interacción con METTL3 y la asociación de cromatina.

Principales resultados:

El knockout de METTL3 alteró la formación de heterocromatina en las IAP y aumentó la transcripción de las IAP, lo que indica el papel de METTL3 en la integridad de la heterocromatina de las IAP.
Las transcripciones IAP unidas a METTL3 están metiladas por m6A, interactúan con YTHDC1 y promueven la asociación de cromatina de METTL3.
METTL3 interactúa físicamente con SETDB1 y TRIM28, facilitando su localización a los IAP.

Conclusiones:

La modificación del ARN m6A catalizado por METTL3 es esencial para mantener la integridad de la heterocromatina IAP en las células madre embrionarias de ratón.
Este estudio revela un nuevo mecanismo de regulación de la heterocromatina en los mamíferos que implica la metilación de METTL3 y ARN.

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